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WO2001097832A1 - Pharmaceutical preparations containing cyclosporines and neutral oils - Google Patents

Pharmaceutical preparations containing cyclosporines and neutral oils Download PDF

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Publication number
WO2001097832A1
WO2001097832A1 PCT/EP2001/007037 EP0107037W WO0197832A1 WO 2001097832 A1 WO2001097832 A1 WO 2001097832A1 EP 0107037 W EP0107037 W EP 0107037W WO 0197832 A1 WO0197832 A1 WO 0197832A1
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WO
WIPO (PCT)
Prior art keywords
acid
pharmaceutical composition
composition according
neutral oil
ester
Prior art date
Application number
PCT/EP2001/007037
Other languages
German (de)
French (fr)
Inventor
Norbert KLÖCKER
Original Assignee
Audit Institute For Medical Services And Quality Assurance Gmbh
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from DE2000130378 external-priority patent/DE10030378A1/en
Priority claimed from DE2001101529 external-priority patent/DE10101529A1/en
Application filed by Audit Institute For Medical Services And Quality Assurance Gmbh filed Critical Audit Institute For Medical Services And Quality Assurance Gmbh
Priority to AU66087/01A priority Critical patent/AU6608701A/en
Publication of WO2001097832A1 publication Critical patent/WO2001097832A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/12—Cyclic peptides, e.g. bacitracins; Polymyxins; Gramicidins S, C; Tyrocidins A, B or C
    • A61K38/13—Cyclosporins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4858—Organic compounds

Definitions

  • the invention relates to a pharmaceutical composition consisting of a water-insoluble or sparingly water-soluble active ingredient and neutral oil, it being possible to dispense with the use of solubilizers, additional components, and with alcohols and heating.
  • the invention relates to pharmaceutical compositions consisting of a cyclosporin and neutral oil.
  • compositions known hitherto for the use of cyclosporins contain alcoholic solutions or oily solutions.
  • Known oily solutions of cyclosporins are based on the use of paraffin oil, corn oil, fish oil, sesame oil, peanut oil, castor oil, etc. These have the disadvantage of a very high viscosity, which often makes sterile filtration impossible, or only by adding further components and / or by heating. This is lengthy and expensive. In addition, cleaning the filling system and validating the cleaning process during production is lengthy and costly. In addition, the known oily solutions are often unable to dissolve cyclosporin in therapeutically necessary concentrations, or only by adding solubilizers and / or further components and / or heating.
  • the object of the invention is to provide a pharmaceutical composition for the use of cyclosporins in the form of a solution, it being possible to dispense with the use of solubilizers and / or further components and / or heating, the composition being sterile filterable and stable.
  • the object is achieved according to the invention and unexpectedly by a pharmaceutical composition which contains at least one cyclosporin dissolved in a neutral oil.
  • the composition is essentially anhydrous.
  • Essentially water-free is understood here to mean a water content in the composition which can result from water of hydration, water of crystallization and / or residual moisture in the neutral oil, the active ingredients and / or the auxiliaries.
  • the composition is easy to filter, so that sterile filtration (0.2 ⁇ m pore size) can be used to produce a sterile solution without great effort.
  • the stability is very high.
  • the tolerance of the oil solution according to the invention is very good.
  • the production is simple and inexpensive, since no further additives are necessary and the neutral oil as a carrier is cheap.
  • neutral oil means medium-chain triglycerides. These can be achieved by esterifying medium-chain fatty acids such as Capronic acid, capric acid, caprylic acid, lauric acid, myristic acid, linoleic acid and succinic acid, in particular capric acid, caprylic acid, linoleic acid and succinic acid can be obtained with glycerol and / or propylene glycol (Miglyol 810, 812, 818, 840).
  • the viscosity of the neutral oils used is 1-40 mPa s, in particular 5-20 mPa s, a viscosity of 8-15 mPa s is preferred.
  • the preferred neutral oil according to the invention is Miglyol 840 and / or neutral oil according to DAB and Miglyol 812.
  • compositions according to the invention include formulations for topical application, for example on the eye, and for oral, rectal and parenteral application.
  • the pharmaceutical composition according to the invention can contain, for example, cyclosporin A, B, C, D and G, dihydrocyclosporins, isocyclosporins and / or their derivatives, in particular cyclosporin A, as an active ingredient component from the group of immunosuppressants.
  • the pharmaceutical composition according to the invention can have an active ingredient content of 0.01-20% by weight, in particular 0.05-15% by weight, preferably 0.1-10% by weight. The percentages relate to the total amount of the pharmaceutical composition.
  • the pharmaceutical composition according to the invention can optionally also contain antioxidants and / or sorption promoters such as, for example, tocopherol, ⁇ -tocopherol ester, ascorbic acid, ascorbic acid ester (myristate, palmitate and stearate), ⁇ -carotene, cysteine, acetylcysteine, folic acid (vitamin B 2 - Group), phytic acid, ice and / or trans-urocanoic acid, carnosine (N-ß-alanine-L-histidine), histidine, flavones, flavonoids, lycopene, tyrosine, glutathione, glutanate esters, ⁇ -lipoic acid, ubiquinone, nordihydroguaiaretic acid (NDGA ), Gallic acid esters (ethyl, propyl, octyl, dodecyl gallate), phosphoric acid derivatives (monophosphates, polyphosphates
  • the content of the optionally added antioxidants and / or sorption promoters can be 0.001-2% by weight, based on the total amount of the pharmaceutical composition.
  • the pharmaceutical composition according to the invention can contain water-insoluble or poorly water-soluble corticoids, androgens, estrogens, progestogens, sympatholytics / sympathomimetics, cholinergics / anticholinergics, weaning agents, immunosuppressants, virustatics, anal gels as possible active ingredient components.
  • Further active ingredients to be used according to the invention are from the group of corticoids, for example beclomethasone dipropionate, budesonide base, dexamethasone, hydrocortisone, flunisolide, prednisone, triamcinolone acetonide, methylprednisolone, Fluticasone, betamethasone, deflazacort, cortisone, cortisone acetate, prednilyden, cloprednol, fluocortolone-21-hexanoate and / or their derivatives, in particular prednisone, dexamethasone, beclomethasone dipropionate and / or budesonide base, from the group of androgens and testosterone and testosteronone, eg testonone and testosterone, for example testosterone and testosterone their derivatives, in particular testosterone, from the group of estrogens, for example estradiol, estradiol benzoate, estradiol valerate, estradi
  • composition for soft gelatin capsules Composition for soft gelatin capsules
  • composition for hard gelatin capsules Composition for hard gelatin capsules
  • composition for injection concentrate Composition for injection concentrate

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Epidemiology (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Engineering & Computer Science (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Immunology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

The invention relates to a pharmaceutical preparation that specifically contains cyclosporines and neutral oils. The use of solubilizers, additional components or alcohols can be avoided and the preparation requires no heating.

Description

PHARMAZEUTISCHE ZUBEREITUNGEN ENTHALTEND CYCLOSPORINE UND NEUTRALOLE PHARMACEUTICAL PREPARATIONS CONTAINING CYCLOSPORINE AND NEUTRALOL
Die Erfindung betrifft eine pharmazeutische Zusammensetzung, bestehend aus einem wasserunlöslichen oder schwer wasserlöslichem Wirkstoff und Neutralöl, wobei auf die Verwendung von Lösungsvermittlern, zusätzlichen Komponenten, sowie auf Alkohole und Erhitzen verzichtet werden kann.The invention relates to a pharmaceutical composition consisting of a water-insoluble or sparingly water-soluble active ingredient and neutral oil, it being possible to dispense with the use of solubilizers, additional components, and with alcohols and heating.
Insbesondere betrifft die Erfindung pharmazeutische Zusammensetzungen bestehend aus einem Cyclosporin und Neutralöl.In particular, the invention relates to pharmaceutical compositions consisting of a cyclosporin and neutral oil.
Die bisher zur Anwendung von Cyclosporinen bekannten pharmazeutischen Zusammensetzungen beinhalten alkoholische Lösungen bzw. ölige Lösungen.The pharmaceutical compositions known hitherto for the use of cyclosporins contain alcoholic solutions or oily solutions.
Bekannte ölige Lösungen von Cyclosporinen beruhen auf der Verwendung von Paraffinöl, Maisöl, Fischöl, Sesamöl, Erdnussöl, Rizinusöl, etc. Diese haben den Nachteil einer sehr hohen Viskosität, welche eine Sterilfiltration oft unmöglich macht, oder erst durch Zugabe weiterer Komponenten und/ oder durch Erhitzung. Dies ist langwierig und teuer. Zudem ist die Reinigung des Abfüllsystems und die Validierung des Reinigungsvorganges bei der Produktion langwierig und kostenintensiv. Zudem sind die bekannten öligen Lösungen häufig nicht in der Lage Cyclosporin in therapeutisch notwendigen Konzentrationen zu lösen, oder erst durch Zugabe von Lösungsvermittlern und/oder weiterer Komponenten und/oder Erhitzen.Known oily solutions of cyclosporins are based on the use of paraffin oil, corn oil, fish oil, sesame oil, peanut oil, castor oil, etc. These have the disadvantage of a very high viscosity, which often makes sterile filtration impossible, or only by adding further components and / or by heating. This is lengthy and expensive. In addition, cleaning the filling system and validating the cleaning process during production is lengthy and costly. In addition, the known oily solutions are often unable to dissolve cyclosporin in therapeutically necessary concentrations, or only by adding solubilizers and / or further components and / or heating.
Die Aufgabe der Erfindung ist es nun, eine pharmazeutische Zusammensetzung zur Anwendung von Cyclosporinen in Form einer Lösung bereitzustellen, wobei auf die Verwendung von Lösungsvermittlern und/oder weiterer Komponenten und/oder Erhitzen verzichtet werden kann, die Zusammensetzung sterilfiltrierbar und stabil ist. Die Aufgabe wird erfindungsgemäß und unerwartet durch eine pharmazeutische Zusammensetzung gelöst, die mindestens ein Cyclosporin gelöst in einem Neutralöl enthält. Die Zusammensetzung ist im wesentlichen wasserfrei.The object of the invention is to provide a pharmaceutical composition for the use of cyclosporins in the form of a solution, it being possible to dispense with the use of solubilizers and / or further components and / or heating, the composition being sterile filterable and stable. The object is achieved according to the invention and unexpectedly by a pharmaceutical composition which contains at least one cyclosporin dissolved in a neutral oil. The composition is essentially anhydrous.
Als im wesentlichen wasserfrei wird hier ein Wassergehalt in der Zusammensetzung verstanden, der durch Hydratwasser, Kristallwasser und/ oder Restfeuchtigkeit des Neutralöls, der Wirkstoffe und/ oder der Hilfsstoffe herrühren kann.Essentially water-free is understood here to mean a water content in the composition which can result from water of hydration, water of crystallization and / or residual moisture in the neutral oil, the active ingredients and / or the auxiliaries.
Die Zusammensetzung ist gut filtrierbar, so daß durch eine Sterilfiltration (0,2 μm Porengröße) ohne großen Aufwand eine sterile Lösung hergestellt werden kann. Die Stabilität ist sehr hoch.The composition is easy to filter, so that sterile filtration (0.2 μm pore size) can be used to produce a sterile solution without great effort. The stability is very high.
Zudem ist die Verträglichkeit der erfindungsgemäßen Öllösung sehr gut. Die Herstellung ist einfach und kostengünstig, da keine weiteren Zusätze nötig sind und das Neutralöl als Träger billig ist.In addition, the tolerance of the oil solution according to the invention is very good. The production is simple and inexpensive, since no further additives are necessary and the neutral oil as a carrier is cheap.
Unter dem Begriff Neutralöl werden mittelkettige Triglyceride verstanden. Diese können durch eine Veresterung von mittelkettige Fettsäuren wie z.B. Capron-, Caprin-, Capryl-, Laurin-, Myristin-, Linol- und Bernsteinsäure, insbesondere Caprin-, Capryl-, Linol- und Bernsteinsäure mit Glycerin und/ oder Propylenglykol erhalten werden (Miglyol 810, 812, 818, 840). Die Viskosität der verwendeten Neutralöle beträgt 1-40 mPa s, insbesondere 5-20 mPa s, bevorzugt wird eine Viskosität von 8-15 mPa s. Das bevorzugt verwendete erfindungsgemäße Neutralöl ist Miglyol 840 und/oder Neutralöl nach DAB sowie Miglyol 812.The term neutral oil means medium-chain triglycerides. These can be achieved by esterifying medium-chain fatty acids such as Capronic acid, capric acid, caprylic acid, lauric acid, myristic acid, linoleic acid and succinic acid, in particular capric acid, caprylic acid, linoleic acid and succinic acid can be obtained with glycerol and / or propylene glycol (Miglyol 810, 812, 818, 840). The viscosity of the neutral oils used is 1-40 mPa s, in particular 5-20 mPa s, a viscosity of 8-15 mPa s is preferred. The preferred neutral oil according to the invention is Miglyol 840 and / or neutral oil according to DAB and Miglyol 812.
Die erfindungsgemäßen pharmazeutischen Zusammensetzungen umfassen sowohl Formulierungen zur topischen Applikation, wie zum Beispiel am Auge, als auch zur oralen, rektalen und parenteralen Applikation.The pharmaceutical compositions according to the invention include formulations for topical application, for example on the eye, and for oral, rectal and parenteral application.
Die erfindungsgemäße pharmazeutische Zusammensetzung kann aus der Gruppe der Immunsuppressiva z.B. Cyclosporin A, B, C, D und G, Dihydrocyclosporine, Isocyclosporine und / oder deren Derivate, insbesondere Cyclosporin A als Wirkstoffkomponente enthalten. Die erfindungsgemäße pharmazeutische Zusammensetzung kann einen Wirkstoffgehalt von 0,01-20 Gew.%, insbesondere 0,05-15 Gew.%, bevorzugt 0,1- 10 Gew.% aufweisen. Die Prozentangaben beziehen sich auf die Gesamtmenge der pharmazeutischen Zusammensetzung.The pharmaceutical composition according to the invention can contain, for example, cyclosporin A, B, C, D and G, dihydrocyclosporins, isocyclosporins and / or their derivatives, in particular cyclosporin A, as an active ingredient component from the group of immunosuppressants. The pharmaceutical composition according to the invention can have an active ingredient content of 0.01-20% by weight, in particular 0.05-15% by weight, preferably 0.1-10% by weight. The percentages relate to the total amount of the pharmaceutical composition.
Die erfindungsgemäße pharmazeutische Zusammensetzung kann gegebenenfalls noch Antioxidantien und / oder Sorptionsförderer wie z.B. -Tocopherol, α- Tocopherolester, Ascorbinsäure, Ascorbinsäureester (-myristat, -palmitat und - stearat), ß-Carotin, Cystein, Acetylcystein, Folsäure (Vitamin-B2-Gruppe), Phytinsäure, eis- und/ oder trans-Urocansäure, Karnosin (N-ß-Alanin-L-Histidin), Histidin, Flavone, Flavonoide, Lycopin, Tyrosin, Gluthation, Gluthationester, α- Liponsäure, Ubichinon, Nordihydroguaiaretsäure (NDGA), Gallussäureester (Ethyl-, Propyl-, Octyl-, Dodecylgallat), Phosphorsäurederivate (Monophosphate, Polyphosphate), Butylhydroxytoluol (BHT), Butylhydroxyanisol (BHA), Tetraoxydimethylbiphenyl (TDBP), Polyalkohole, Citronensäure, Weinsäure, Edetinsäure (EDTA als Di-Na- oder Di-Na-Ca-Salz), Coniferylbenzoat und/ oder deren Derivate enthalten, die die Aufnahme durch die Cutis und/oder Schleimhäute fördern und/ oder das Neutralöl zusätzlich stabilisieren.The pharmaceutical composition according to the invention can optionally also contain antioxidants and / or sorption promoters such as, for example, tocopherol, α-tocopherol ester, ascorbic acid, ascorbic acid ester (myristate, palmitate and stearate), β-carotene, cysteine, acetylcysteine, folic acid (vitamin B 2 - Group), phytic acid, ice and / or trans-urocanoic acid, carnosine (N-ß-alanine-L-histidine), histidine, flavones, flavonoids, lycopene, tyrosine, glutathione, glutanate esters, α-lipoic acid, ubiquinone, nordihydroguaiaretic acid (NDGA ), Gallic acid esters (ethyl, propyl, octyl, dodecyl gallate), phosphoric acid derivatives (monophosphates, polyphosphates), butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), tetraoxydimethylbiphenyl (TDBP), polyalcohols, citric acid, tartaric acid EDA, as tartaric acid Na or di-Na-Ca salt), coniferyl benzoate and / or their derivatives which promote absorption by the cutis and / or mucous membranes and / or additionally stabilize the neutral oil.
Der Gehalt der gegebenenfalls zugefügten Antioxidantien und / oder Sorptionsförderer kann 0,001-2 Gew.%, bezogen auf die Gesamtmenge der pharmazeutischen Zusammensetzung, betragen.The content of the optionally added antioxidants and / or sorption promoters can be 0.001-2% by weight, based on the total amount of the pharmaceutical composition.
Die erfindungsgemäße pharmazeutische Zusammensetzung kann wasserunlösliche oder schwer wasserlösliche Corticoide, Androgene, Östrogene, Gestagene, Sympatholytika/Sympathomimetika, Cholinergika/Anticholinergika, Entwöhnungsmittel, Immunsuppressiva, Virustatika, Analgeltika als mögliche Wirkstoffkomponenten enthalten.The pharmaceutical composition according to the invention can contain water-insoluble or poorly water-soluble corticoids, androgens, estrogens, progestogens, sympatholytics / sympathomimetics, cholinergics / anticholinergics, weaning agents, immunosuppressants, virustatics, anal gels as possible active ingredient components.
Weitere erfindungsgemäß zu verwendende Wirkstoffe sind aus der Gruppe der Corticoide z.B. Beclomethasondipropionat, Budesonidbase, Dexamethason, Hydrocortison, Flunisolid, Prednison, Triamcinolonacetonid, Methylprednisolon, Fluticason, Betamethason, Deflazacort, Cortison, Cortisonacetat, Prednilyden, Cloprednol, Fluocortolon-21-hexanoat und/oder deren Derivate, insbesondere Prednison, Dexamethason, Beclomethasondipropionat und/oder Budesonidbase, aus der Gruppe der Androgene z.B. Testosteron, Testosteronundecanoat, Androsteron und/ oder deren Derivate, insbesondere Testosteron, aus der Gruppe der Östrogene z.B. Estradiol, Estradiolbenzoat, Estradiolvalerat, Estradioldipropionat, Estron, Estriol, Diethylstilbestrol,Further active ingredients to be used according to the invention are from the group of corticoids, for example beclomethasone dipropionate, budesonide base, dexamethasone, hydrocortisone, flunisolide, prednisone, triamcinolone acetonide, methylprednisolone, Fluticasone, betamethasone, deflazacort, cortisone, cortisone acetate, prednilyden, cloprednol, fluocortolone-21-hexanoate and / or their derivatives, in particular prednisone, dexamethasone, beclomethasone dipropionate and / or budesonide base, from the group of androgens and testosterone and testosteronone, eg testonone and testosterone, for example testosterone and testosterone their derivatives, in particular testosterone, from the group of estrogens, for example estradiol, estradiol benzoate, estradiol valerate, estradiol dipropionate, estrone, estriol, diethylstilbestrol,
Diethylstilbestroldimethylether, Diethylstilbestroldiphosphat,Diethylstilbestrol dimethyl ether, diethylstilbestrol diphosphate,
Diethylstilbestroldipropionat und/ oder deren Derivate, insbesondere Estradiol und Estriol, aus der Gruppe der Gestagene z.B. Progesteron und/ oder dessen Derivate, aus der Gruppe der Sympatholytika/ Sympathomimetika z.B. Acebutolol, Adimolol, Adrenalin, Albuterol, Alpenolol, Amosulalol, Arotinolol, Atenolol, Bambuterol, Betaxolol, Bevantolol, Bisoprolol, Bitolterol, Bopindolol, Broxaterol, Bucindolol, Bucumolol, Bufuralol, Bunitrolol, Bupranolol, Butofilolol, Carazolol, Carbuterol, Carteolol, Carvedilol, Celiprolol, Cetamolol, Cicloprolol, Clenbuterol, Cloranolol, Crateolol, Celiprolol, Dihydroergotamin, Dillydroergotamintartrat,Diethylstilbestrol dipropionate and / or their derivatives, in particular estradiol and estriol, from the group of gestagens e.g. Progesterone and / or its derivatives, from the group of sympatholytics / sympathomimetics e.g. Acebutolol, Adimolol, Adrenalin, Albuterol, Alpenolol, Amosulalol, Arotinolol, Atenolol, Bambuterol, Betaxolol, Bevantolol, Bisoprolol, Bitolterol, Bopindolol, Broxaterol, Bucindolol, Bucumolol, Bufuralol, Buprololololol, Buprololololol, Bofilrololololol, Buprololololol, Bofilrolololol Celiprolol, Cetamolol, Cicloprolol, Clenbuterol, Cloranolol, Crateolol, Celiprolol, Dihydroergotamine, Dillydroergotamine Tartrate,
Dihydroergotaminmesylat, Dilevalol, Dopamin, Dobutamin, Etilefrin, Epanolol, Esatenolol, Esmolol, Fenetyllin, Fenoterol, Formoterol, Ibuterol, Isoprenalin, Labetalol, Landiolol, Levobetaxolol, Levobunolol, Levosalbutamol, Mabuterol, Mepindolol, Metipranolol, Metoprolol, Morazon, Nadotol, Nebivolol, Nipradilol, Norfenefrin, Noradrenalin, Oxprenolol, Penbutolol, Picumeterol, Pimolol, Pindolol, Pirbuterol, Phenmetrazin Phenylephedrin, Phentolamin, Phenoxybenzamin, Prazosin, Procaterol, Propanolol, Rimiterol, Reproterol, Salbutamol, Salmeterol, Sotalol, Sulfonterol, Terbutalin, Tertatolol, Tienoxolol, Tilisolol, Timolol, Toliprolol, Tolubuterol, und/ oder deren Derivate, insbesondere Timolol, aus der Gruppe der Cholinergika/Anticholinergika z.B. Pilocarpin, Ipratropiurn, Oxitropium, Atropin, Scopolaminbase und/ oder deren Derivate, insbesondere Pilocarpin, Scopolaminbase und Atropin, aus der Gruppe der Entwöhnungsmittel z.B. Naioxon, Naitrexon und/ oder deren Derivate, insbesondere Naioxon, aus der Gruppe der Virustatika z.B. Aciclovir und/oder deren Derivate, insbesondere Aciclovir, und aus der Gruppe der Analgetika z.B. Alminoprofen, Bermoprofen, Carprofen, Dexibuprofen, Dexketoprofen, Fenoprofen, Flobufen, Flunoxaprofen, Flurbiprofen, Loxoprofen, Pelobiprofen, Pranoprofen, Pentazocin, Tilnoprofen, Ximoprofen, Zaltroprofen, Dextropropoxyphen, Phenylbutazon, Mofebutazon, Diclofenac, Aceclofenac, Amfenac, Bromfenac, Clidanac, Etodolac, Felbinac, Fentiazac, Ketolerac, Lonazolac, Mofezolac, Oxindanac, Tifurac, Indomethacin, Acemetacin, Piroxicam, Ampiroxicam, Meloxicam, Isoxicam, Lornoxicam, Tenoxicain, Butorphanol, Buprenorphin, Morphin, Hydromorphon, Dihydrocodein, Oxycodon, Piritramid, Pethidin, Pentazocin, Levomethadon, Tramadol, Fentanyl, Sufentanil, und/oder dessen Derivate, insbesondere Ketolerac.Dihydroergotamine Mesylate, Dilevalol, Dopamine, Dobutamine, Etilefrin, Epanolol, Esatenolol, Esmolol, Fenetylline, Fenoterol, Formoterol, Ibuterol, Isoprenaline, Labetalol, Landiolol, Levobetaxolol, Levobunolol, Levosalbutamol, Mabuterolololol, Mabuterol, Mobuterol Nipradilol, norfenefrin, noradrenaline, oxprenolol, penbutolol, picumeterol, pimolol, pindolol, pirbuterol, phenmetrazine phenylephedrine, phentolamine, phenoxybenzamine, prazosin, procaterol, propanolol, rimiterol, reproterol, salbutonololol, tolololololol, tololololol, tololololol, tolololol, tolol , Timolol, Toliprolol, Tolubuterol, and / or their derivatives, in particular timolol, from the group of cholinergics / anticholinergics, for example pilocarpine, ipratropium, oxitropium, atropine, scopolamine base and / or their derivatives, in particular pilocarpine, scopolamine base and atropine, from the group of Weaning agents, eg Naioxon, Naitrexon and / or their derivatives, in particular Naioxon, a us from the group of antivirals, for example acyclovir and / or their derivatives, in particular acyclovir, and from the group of analgesics, for example alminoprofen, bermoprofen, carprofen, dexibuprofen, dexketoprofen, fenoprofen, flobufen, flunoxaprofen, flurbiprofen, loxoprofen, pelobiprofen, pranoprofen, pentazocin, tilnoprofen, ximoprofen, daltroprofonene, zaltroprofeno Bromfenac, Clidanac, Etodolac, Felbinac, Fentiazac, Ketolerac, Lonazolac, Mofezolac, Oxindanac, Tifurac, Indomethacin, Acemetacin, Piroxicam, Ampiroxicam, Meloxicam, Isoxicam, Lornoxicam, Tenoxicin, Hydrocodonium, Morphodonium, Morphodonium, Morphodonium, Morphodonium Pethidine, pentazocin, levomethadone, tramadol, fentanyl, sufentanil, and / or its derivatives, especially ketolerac.
Die Erfindung wird durch nachstehende Beispiele näher erläutert, ohne aber den Erfindungsumfang damit einzuschränken.The invention is illustrated in more detail by the following examples, but without restricting the scope of the invention.
Beispiel 1 :Example 1 :
Zusammensetzung für Weichgelatine-KapselnComposition for soft gelatin capsules
10 mg Cyclosporin A werden in 90 ml Miglyol 840 gelöst. Diese Öllösung wird über einen 0,2 μm Pall Fluorodyne II Grad DFL Pharmaqualität Filter steril filtriert und in10 mg cyclosporin A are dissolved in 90 ml Miglyol 840. This oil solution is sterile filtered through a 0.2 μm Pall Fluorodyne II grade DFL pharmaceutical grade filter and in
Weichgelatine-Kapseln gefüllt.Soft gelatin capsules filled.
Beispiel 2:Example 2:
Zusammensetzung für Hartgelatine-KapselnComposition for hard gelatin capsules
10 mg Cyclosporin A werden in 90 ml Miglyol 840 gelöst. Diese Öllösung wird über einen 0,2 μm Pall Fluorodyne II Grad DFL Pharmaqualität Filter steril filtriert und in Hartgelatine-Kapseln gefüllt.10 mg cyclosporin A are dissolved in 90 ml Miglyol 840. This oil solution is sterile filtered through a 0.2 μm Pall Fluorodyne II grade DFL pharmaceutical grade filter and filled into hard gelatin capsules.
Beispiel 3:Example 3:
Zusammensetzung für Injektions-KonzentratComposition for injection concentrate
10 mg Cyclosporin A werden in 990 ml Miglyol 840 gelöst. Diese Öllösung wird über einen 0,2 μm Pall Fluorodyne II Grad DFL Pharmaqualität Filter steril filtriert und in Ampullen gefüllt. 10 mg cyclosporin A are dissolved in 990 ml Miglyol 840. This oil solution is sterile filtered through a 0.2 μm Pall Fluorodyne II grade DFL pharmaceutical grade filter and filled into ampoules.

Claims

Patentansprüche claims
1. Pharmazeutische Zusammensetzung, gekennzeichnet durch mindestens ein Cyclosporin gelöst in Neutralöl.1. Pharmaceutical composition, characterized by at least one cyclosporin dissolved in neutral oil.
2. Pharmazeutische Zusammensetzung nach Anspruch 1 , gekennzeichnet durch mittelkettige Triglyceride als Neutralöl.2. Pharmaceutical composition according to claim 1, characterized by medium-chain triglycerides as neutral oil.
3. Pharmazeutische Zusammensetzung nach Anspruch 2, gekennzeichnet durch Ester, gebildet durch Veresterung von Capron-, Caprin-, Capryl-, Laurin-, Myristin-, Linol- und/ oder Bernsteinsäure mit Glycerin oder Propylenglykol, als mittelkettigen Triglyceride3. Pharmaceutical composition according to claim 2, characterized by esters, formed by esterification of capronic, capric, caprylic, lauric, myristic, linoleic and / or succinic acid with glycerol or propylene glycol, as medium-chain triglycerides
4. Pharmazeutische Zusammensetzung nach Anspruch 2 oder 3, gekennzeichnet durch Ester, gebildet durch Veresterung von Caprin-, Capryl-, Linol- und/ oder Bernsteinsäure mit Glycerin oder Propylenglykol, als mittelkettige Triglyceride.4. Pharmaceutical composition according to claim 2 or 3, characterized by esters, formed by esterification of capric, caprylic, linoleic and / or succinic acid with glycerol or propylene glycol, as medium-chain triglycerides.
5. Pharmazeutische Zusammensetzung nach einem der vorangegangenen Ansprüche, gekennzeichnet durch eine Viskosität des Neutralöls von 1-40 mPa s.5. Pharmaceutical composition according to one of the preceding claims, characterized by a viscosity of the neutral oil of 1-40 mPa s.
6. Pharmazeutische Zusammensetzung nach Anspruch 5, gekennzeichnet durch eine Viskosität des Neutralöls von 5- 20 mPa s.6. Pharmaceutical composition according to claim 5, characterized by a viscosity of the neutral oil of 5- 20 mPa s.
7. Pharmazeutische Zusammensetzung nach Anspruch 5 oder 6, gekennzeichnet durch eine Viskosität des Neutralöls von 8- 15 mPa s.7. Pharmaceutical composition according to claim 5 or 6, characterized by a viscosity of the neutral oil of 8-15 mPa s.
8. Pharmazeutische Zusammensetzung nach Anspruch 7, gekennzeichnet durch α-Tocopherol, α-Tocopherolester, Ascorbinsäure, Ascorbinsäureester, ß- Carotin, Cystein, Acetylcystein, Folsäure, Phytinsäure, eis- und/ oder trans- Urocansäure, Karnosin, Histidin, Flavone, Flavonoide, Lycopin, Tyrosin, Gluthation, Gluthationester, α-Liponsäure, Ubichinon, Nordihydroguaiaretsäure, Gallussäureester, Phosphorsäurederivate, Butylhydroxytoluol,8. Pharmaceutical composition according to claim 7, characterized by α-tocopherol, α-tocopherol ester, ascorbic acid, ascorbic acid ester, β-carotene, cysteine, acetylcysteine, folic acid, phytic acid, ice and / or trans Urocanoic acid, carnosine, histidine, flavones, flavonoids, lycopene, tyrosine, glutation, glutation ester, α-lipoic acid, ubiquinone, nordihydroguaiaretic acid, gallic acid ester, phosphoric acid derivatives, butylated hydroxytoluene,
Butylhydroxyanisol, Tetraoxydimethylbiphenyl, Polyalkohole, Citronensäure, Weinsäure, Edetinsäure (EDTA als Di-Na- oder Di-Na-Ca-Salz),Butylated hydroxyanisole, tetraoxydimethylbiphenyl, polyalcohols, citric acid, tartaric acid, edetic acid (EDTA as di-Na or di-Na-Ca salt),
Coniferylbenzoat und/ oder deren Derivate als Antioxidationsmittel und / oder Sorptionsförderer.Coniferyl benzoate and / or their derivatives as antioxidants and / or sorption promoters.
9. Pharmazeutische Zusammensetzung nach einem der vorstehenden Ansprüche enthaltend Cyclosporin A.9. Pharmaceutical composition according to one of the preceding claims containing cyclosporin A.
10. Pharmazeutische Zusammensetzung nach einem der vorangegangenen Ansprüche, wobei das Neutalöl entweder Miglyol 840 oder Miglyol 812 ist. 10. Pharmaceutical composition according to one of the preceding claims, wherein the neutral oil is either Miglyol 840 or Miglyol 812.
PCT/EP2001/007037 2000-06-21 2001-06-21 Pharmaceutical preparations containing cyclosporines and neutral oils WO2001097832A1 (en)

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Applications Claiming Priority (4)

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DE2000130378 DE10030378A1 (en) 2000-06-21 2000-06-21 New pharmaceutical composition for topical application of water-insoluble and / or poorly water-soluble active ingredients
DE10030378.1 2000-06-21
DE2001101529 DE10101529A1 (en) 2001-01-15 2001-01-15 A solution of cyclosporin in neutral oil, preferably medium chain triglyceride, is useful as an immunosuppressive agent
DE10101529.1 2001-01-15

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WO2003055480A1 (en) * 2001-12-21 2003-07-10 Pharmaconsult Oy Products for use in immunosuppressive therapy containing lipoic acid and a calcineurin inhibitor
WO2004006890A1 (en) * 2002-07-15 2004-01-22 Alcon, Inc. Non-polymeric lipophilic pharmaceutical implant compositions for intraocular use
US20120238536A1 (en) * 2009-11-19 2012-09-20 Novagali Pharma Sa Method for Treating Retinal Conditions Using an Intraocular Tamponade

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Publication number Priority date Publication date Assignee Title
WO2003055480A1 (en) * 2001-12-21 2003-07-10 Pharmaconsult Oy Products for use in immunosuppressive therapy containing lipoic acid and a calcineurin inhibitor
WO2004006890A1 (en) * 2002-07-15 2004-01-22 Alcon, Inc. Non-polymeric lipophilic pharmaceutical implant compositions for intraocular use
CN100355455C (en) * 2002-07-15 2007-12-19 爱尔康公司 Non-polymeric lipophilic pharmaceutical implant compositions for intraocular use
US7678827B2 (en) 2002-07-15 2010-03-16 Alcon, Inc. Non-polymeric lipophilic pharmaceutical implant compositions for intraocular use
US8178576B2 (en) 2002-07-15 2012-05-15 Novartis Ag Non-polymeric lipophilic pharmaceutical implant compositions for intraocular use
US20120238536A1 (en) * 2009-11-19 2012-09-20 Novagali Pharma Sa Method for Treating Retinal Conditions Using an Intraocular Tamponade
US9616016B2 (en) 2009-11-19 2017-04-11 Santen Sas Method for treating retinal conditions using an intraocular tamponade

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